Context: Pediatric solid tumors include a heterogeneous group of tumors, and the burden of these tumors, especially from resource-challenged countries, is not well described. AIMS: The aim of this study was to describe the distribution of solid tumors in children and the treatment outcome of Wilms tumor and hepatoblastoma. Patients and Methods: All patients under 15 years of age with histologically confirmed tumors presenting at a tertiary cancer center from January 2012 to December 2016 were identified from the hospital database. Patients with lymphomas, bone, and central nervous tumors were excluded. The demographic profile including age, sex distribution, and the treatment received were recorded for all patients. Results: The mean age of the eligible 1944 patients was 5.7 years with majority (57.3%) in the 0–4 years age group. The male-to-female ratio was 1.4:1 with a male predominance in all tumors except germ cell tumors. Soft tissue tumors were the most common tumors followed by neuroblastoma and renal tumors, whereas liver tumors formed only 6.7% of all tumors. Seventy percent of the patients received treatment completely or partially at our institute, whereas 18.3% had no cancer-directed treatment. The 3-year overall survival of patients with Wilms tumor and hepatoblastoma was 85.4 and 78.5%, respectively. Conclusions: Extracranial and extraosseous pediatric solid tumors include a wide range of tumors with a predilection for male sex and children below 4 years of age. Soft tissue tumors, neuroblastoma, and renal tumors are the most common; the outcomes of Wilms tumor and hepatoblastoma are favorable.

Information regarding the incidence and distribution of a disease in a community is an intricate part of the healthcare planning to guide quality improvement initiatives and policy formulation process.[1] Although there is plenty of data on the incidence and prevalence of infectious diseases in the world, information on epidemiology of malignancies is still lacking. While counties in North America and Europe have stringent population-based cancer registries and cooperative projects such as Automated Childhood Cancer Information System (ACCIS) and EUROCARE,[2] data reporting in India is still in its infancy, especially for pediatric malignancies. Cancer registries that document the incidence of disease are plagued by poor reporting from government hospitals and no reporting by many of the private practitioners, with some population-based studies reporting an incidence of just over a thousand cases in 10 years.[3]

To determine the pattern of distribution of pediatric solid tumors, we evaluated all children <15 years of age with extraosseous and extracranial solid tumors. Secondly, the treatment offered and the outcomes of Wilms tumor and hepatoblastoma are also presented.

» Patients and Methods

Institutional Review Board approval and waiver of consent were taken for the study. All patients under 15 years with histologically confirmed disease presenting at Tata Memorial Hospital (TMH) from January 2012 to December 2016 were identified from the hospital database. Patients without a definite diagnosis of malignancy irrespective of the clinicoradiological features and prior therapy for suspected or proven malignancy elsewhere were excluded from the analysis. Patients with central nervous system and bone tumors were also excluded from this study. Similarly, lymphomas and other hematolymphoid disease were also excluded. The age, sex, histopathology, prior treatment, and treatment offered at our hospital were recorded for all patients. The treatment was categorized into four groups as per the Consolidated Report of Hospital Based Cancer Registries 2007–2011 by the Indian Council of Medical Research.[4]

Prior treatment only:Those patients who have received some or complete cancer-directed treatment before registration and have not received any further treatment at TMH

Prior treatment and treatment at TMH: These are patients who have received cancer-directed treatment prior to registration and have received further treatment at TMH

Treatment only at TMH: Patients who have come for the first time to TMH with or without a confirmed diagnosis of malignancy and have not received any cancer-directed treatment earlier and received complete cancer-directed treatment at TMH

No cancer-directed treatment: This group includes patients who have neither received nor accepted any treatment. It also includes the patients who have not completed any form of treatment, where the treatment status is unknown and have received only supportive care.

All patients underwent a comprehensive clinical evaluation followed by histological confirmation of the disease except retinoblastoma, which were diagnosed based on clinical and radiological features and some liver tumors which were diagnosed with elevated tumor markers and presence of a liver mass. Radiological investigations included computerized tomogram or magnetic resonance imaging. A dedicated pathologist specializing in pediatric solid tumors established the diagnosis for all the solid tumors. The histological confirmation utilized a biopsy or a fine-needle aspiration cytology as appropriate, and patients who underwent a biopsy elsewhere prior to presentation at our center had the histology reviewed. Immunohistochemistry panel was utilized and molecular pathological studies for confirmation of diagnosis in challenging situations or risk and treatment stratification (e.g., MYCN, SYT SSX1, PAX3 FKHR, etc.) were performed. Nuclear imaging including 18F-fluorodeoxyglucose positron emission tomography were utilized judiciously wherever indicated. The diagnostic and therapeutic flowcharts for Wilms tumor and hepatoblastoma are shown in [Figure 1] and [Figure 2]. All treatment decisions were discussed in a tumor board comprising pediatric medical, surgical, and radiation oncologist, a dedicated pediatric radiologist, pathologist, nuclear medicine, and palliative care physician.

A descriptive analysis was performed to evaluate the age and sex distribution of all tumors. For assessing the relative incidence of a given diagnosis, the frequency distribution and its percentage were calculated. To determine age distribution, patients were divided into three equal age groups, i.e., 4 years or less, 5–9 years, and 10–15 years, and the distribution between the three age groups was analyzed. Data collection and analysis was performed using SPSS, version 24.

» Results

A total of 2293 patients have registered in the study period; 148 were found to have no malignancy and 201 patients without histological confirmation of malignancy were excluded. The study cohort, therefore, included 1944 patients with a solid tumor [Table 1]. The youngest patient was 3 days old. The mean age was 5.7 years. The male to female ratio was 1.4:1 with 1139 (58.5%) males and 807 (41.5%) females. Majority of the patients (57.3%) were in the 0–4 age group, while a quarter (25.9%) of the patients belonged to the 10–15 years age group. The number of patients diagnosed each year increased over the time period and the increase was most noticeable in the preceding 2 years for all the tumors [Table 2].

Soft tissue tumors were the most common accounting for 27.4% of all the tumors. Rhabdomyosarcoma constituted 51% and the nonrhabdomyosarcoma formed 49% of all the soft tissue tumors [Table 3]. The predominant histological types of nonrhabdomyosarcoma were extraskeletal Ewing sarcoma, fibromatosis, synovial sarcoma, extrarenal rhabdoid tumors, malignant nerve sheath tumors, inflammatory myofibroblastic tumors, and infantile fibrosarcoma. In 30 patients the sarcoma could not be characterized to a specific lineage. Rhabdomyosarcoma was predominantly seen in less than 4 years children, while the nonrhabdomyosarcoma was common in more than 10 years age group. However, there was a male preponderance in both the groups. Neuroblastoma was the second common tumor (20%) and like retinoblastoma (10.4%) showed a predilection for children <4 years of age.

Renal tumors were the third common tumors and 83% of them were Wilms tumor. The non-Wilms tumor included clear cell sarcoma, renal cell carcinoma, renal Ewing sarcoma, malignant rhabdoid tumor, and congenital mesoblastic nephroma. Germ cell tumors comprised 11.4% of all the tumors with almost an equal distribution at gonadal (51%) and extragonadal (49%) sites. The gonadal tumors were commonly seen in females above 10 years of age, while the extragonadal tumors were seen in children <4 years; however, they did not show a gender predilection. Liver tumors formed only 6.7% of all the solid tumors and 76% of them were hepatoblastoma. The nonhepatoblastoma liver tumors included hepatocellular carcinoma, infantile hepatic hemangioma, mesenchymal hamartoma, extrarenal rhabdoid tumor, and hepatic adenoma. Among the 231 (11.9%) patients classified as miscellaneous tumors, thyroid gland, nasopharyngeal, salivary gland, adrenocortical, colon, and pancreatic cancers were seen in decreasing order of frequency.

Overall, 45.2% had treatment only at TMH and additional 25% who had prior treatment also received treatment in TMH [Table 4]. 11.5% had prior treatment only and 18.3% had no cancer-directed treatment. Patients with neuroblastoma, hepatoblastoma, and retinoblastoma most often did not receive any cancer-directed treatment. Patients with germ cell tumors usually (51%) had some prior treatment and 59% of them received further treatment at TMH. 80% and 75% of previously treated soft tissue tumors and renal tumors received further treatment in TMH. Of the 45 patients with retinoblastoma who did not receive any cancer-directed treatment, 20 patients had refused treatment and the remaining patients had advanced metastatic disease and were offered supportive care only. Surgery, either alone or in combination with chemotherapy and/or radiotherapy was offered to more than 80% of the 118 patients who received treatment only at TMH.

Table 4: Distribution of the treatment of the solid tumors as per the Consolidated Report of Hospital-Based Cancer Registries 2007-2011 by the Indian Council of Medical Research

Of the 196 patients with Wilms tumor, 31 presented with recurrent disease, 2 had metachronous bilateral disease, and the remaining 163 patients had primary Wilms tumor. Survival analysis was performed for the 70 patients treated in the initial 3 years (2012–2014). At a median follow-up of 38 months, the 3-year overall survival for all stages of Wilms tumor is 85.4% [Figure 3]. Of the 96 patients with hepatoblastoma, 2 presented with recurrent disease and the remaining 94 patients had primary tumors. Forty-five patients were seen in the initial 3 years (2012–2014) of which four were offered best supportive care due to advanced metastatic disease and four were offered chemotherapy only since liver transplant was required for local therapy which was not feasible due to logistic reasons. The remaining patient were offered curative treatment, and at a median follow-up of 38 months, the 3-year overall survival is 78.5% [Figure 4].

The exact incidence of most childhood solid tumors in India is not known, despite children <15 years forming 35% of the Indian population. Lack of information among patients and parents about the signs and symptoms of childhood cancer, relying on nonmedical forms of treatment, lack of finances, untrained professionals at a primary care center, lack of laboratory, and diagnostic imaging equipment all factor in suboptimal reporting.[1] Additionally, a significant number of cases go unreported in the developing world due to poor data collection and reporting infrastructure. The lack of expertise often leads to improper staging and inadequate treatment, which contributes to the poorer survival observed in developing countries as compared to the high-income countries. In this study, we present the distribution of various childhood solid tumors seen in the pediatric solid tumor Disease Management Group (DMG) of the largest tertiary cancer center in India that caters to almost the entire country. The concept of DMG has allowed the alliance of different specialties for treatment of an index tumor. The pediatric solid tumor DMG includes dedicated clinicians which are integral in the diagnosis, therapy, care after completion of therapy, and palliative care for advanced tumors in this age group. Bone tumors, central nervous system tumors, and lymphomas were excluded for logistic reasons since they are managed in a different DMG.

This study included patients <15 years of age with histological confirmation of malignancy seen over duration of 5 years, yielding an average of 389 cases per year. Addition of the patients who were not included due to lack of histological confirmation of malignant disease despite clinicoradiological evidence or history of prior treatment could have further increased these numbers. Also, the number of new cancer cases has shown an increasing trend which was very clear in the preceding 2 years. This may be due to increase in referral and also due to the availability of a robust holistic support system established at our center which takes care of the various needs such as accommodation, nutrition, infection prevention, and importantly for the initial funding for the diagnostic test and later for sustenance of therapy through the funds generation from a dedicated social workforce. However, even these large numbers of cases do not indicate the exact incidence of the pediatric solid tumors in our country, although the information is useful in revealing the patterns of these tumors. A direct comparison with other studies reporting on pediatric solid tumors is not feasible as these studies have included bone, central nervous system tumors, and even lymphomas.[5],[6],[7],[8]

The soft tissue tumors showed a significant higher incidence in our population when compared with other studies accounting for 27.5% of all tumors. However, this may be a relative increase considering that bone and central nervous system tumor were excluded. There was almost similar distribution of rhabdomyosarcoma and the nonrhabdomyosarcoma in our study; however, there was age difference in their incidence. Rhabdomyosarcoma was common in the <4 years age group, while the nonrhabdomyosarcoma was more common in children >10 years of age. More than 40% with soft tissue tumor had a prior treatment and 80% of these required additional treatment, mostly in the form of revision surgery and/or radiotherapy. The soft tissue tumors due to their presentation as unpresumptuous well-circumscribed masses are often misdiagnosed, and consequently, their evaluation and treatment are suboptimal. We have previously reported 48% of nonrhabdomyosarcoma soft tissue tumors presenting after an unplanned excision, and 46% of these patients had residual disease, thereby necessitating revision surgery.[9]

Renal tumors were the third common tumor and Wilms accounted for 83% of all the tumors. Tremendous advances have been made over the past few decades in the treatment of Wilms tumor and evidently, the outcome has significantly improved. Our data also confirm the excellent survival of patients with Wilms tumor, although there is a scope to improve further. Almost 50% of the patients had some form of treatment, predominantly surgery, since renal tumors are unhesitatingly operated by all cadres of surgeons, including pediatric, general, and urosurgeons. Subsequently, 75% of the patients are referred for adjuvant chemotherapy and radiotherapy and for the treatment of relapsed disease.

The highest incidence (50%) of prior treatment was in patients with germ cell tumor; mostly in the form of surgery, probably due to the easy surgical access especially to the testis and the sacrococcygeal region. The highest incidence of no cancer-directed treatment was with neuroblastoma and liver tumors. The large burden of disease, suboptimal nutritional status, toxicity of the treatment, and poor family motivation are the prime reasons for no cancer-directed therapy in patients with neuroblastoma. Among the liver tumors, PRETEXT 4 disease, extensive metastases, and hepatocellular carcinoma were the predominant reasons for no cancer-directed treatment. None of the patients with hepatocellular carcinoma in this study could be offered surgery in view of locally advanced and metastatic disease. Patients with initial PRETEXT 4 who did not respond well to preoperative chemotherapy were referred for liver transplant to specialized centers; however, most did not pursue for various reasons. Nonetheless, the outcomes in other patients with hepatoblastoma were favorable. The need for surgery either alone or in combination with chemotherapy and/or radiotherapy in more than 80% of the patients with retinoblastoma signifies the advanced stages of disease they present with.

The mortality and disability due to cancer can be significantly reduced by early diagnosis and treatment. In order to achieve this, the public health system of the country needs country-specific epidemiological data regarding the disease in the population.[1] Though the outcomes of all the tumors are not provided, which is a limitation to this study, the distribution patterns of various pediatric solid tumors and the treatment received shows the burden and referral patterns in our institute. An assiduous endeavor of our institution is to provide detailed assessment of individual pediatric solid tumors in the near future to better illustrate the cancer patterns of Indian children.

» Conclusion

Extracranial and extraosseous pediatric solid tumors include a wide range of tumors with a predilection for male sex and children <4 years of age. Soft tissue tumors, neuroblastoma, and renal tumors are the most common tumors, and the outcomes of Wilms tumor and hepatoblastoma are favorable. Public health programs and strategies should be framed using country-specific epidemiological data, for early detection and treatment of disease.